In the lens, apoptotic-like pathways guide differentiation initiation of epithelial cells and maturation of fiber cells. These pathways are able to function as molecular switches in lens differentiation without signaling apoptosis because they are regulated by integrin-linked survival pathways. In this proposal we investigate the ?6 integrin signaling pathways that regulate the apoptotic-like differentiation signals essential to proper lens development. In addition, we propose to study the role of adhesion complexes in regulating the signal that activates nuclei and organelle loss. Our long term goals are to extend the current understanding of the mechanisms of integrin function in lens development and disease. Activation of the canonical mitochondria death pathway is sufficient to signal lens epithelial cells to initiate their differentiation. Concurrent with activation of this apoptotic pathway, and important to its regulation, is the induction of pro-survival molecules such as Bcl-2 and IAP3. Preliminary studies suggest that these survival molecules are induced downstream of an ?6 integrin/IGF-1 receptor (IGF-1R) signaling pathway. In Specific Aim 1 of this proposal we investigate the hypothesis that this ?6 integrin/IGF-1 R coordinated signaling pathway provides a crucial cell survival signal required for lens differentiation initiation. We also identified that the survival signaling mechanism that protects lens cells at later stages of differentiation, when apoptotic like pathways are activated for removal of nuclei and organelles, involves a PI3K/GSK3 signal linked to ?6 integrin. The FGF receptor (FGFR), which can activate the PI3K survival signal, is recruited to ?6 integrin complexes in the zone of fiber cell differentiation, suggesting that FGFR and ?6 integrin participate in a coordinate survival signaling pathway required for fiber cell differentiation. In Specific Aim 2 we examine the hypothesis that an ?6 integrin/FGFR activated PI3K/GSK3 signal protects differentiating lens fiber cells from the apoptotic signals essential to their maturation. The scaffolding function of integrin-linked adhesion complexes can direct the ER to the plasma membrane where the ER resident IP3R Ca (2+) release channel is thought to be regulated by molecules such as Bcl-2. In differentiating lens fiber cells both Bcl-2 and IP3R are associated with paxillin, an integrin-linked scaffolding protein. Inactivation of JNK induces disassociation of Bcl-2 from paxillin and the loss of nuclei and organelles. In Specific Aim 3 we examine the hypothesis that JNK-dependent association of Bcl- 2 with paxillin prevents Ca (2+) release by regulating IP3R channels, and that the loss of Bcl-2 from these complexes upon inactivation of JNK initiates an apoptotic pathway involved in nuclei and organelle loss. These studies will define the survival signaling pathways that regulate normal lens differentiation and development and add to our understanding of congenital lens disorders and the induction of lens disease.